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Abstract

DESCRIPTION (provided by applicant): Experimental manipulation of gene expression is a widely used technique that is crucial to much of modern biomedical research. The ability to control the timing and expression level of recombinant genes is central to the production of recombinant protein for basic research as well as for the synthesis of biological pharmaceuticals. Commercially available systems for controlling gene expression in mammalian cells, whether in laboratory cultures or in whole animals, are dependent on the application of small molecule drugs to induce or repress transcription. These systems suffer from several limitations, including toxicity, off-target effects, lack of precision in relation to timing and loation, and reversibility of induction. Moreover, the cost of the effector drug and necessary drug-free media can be burdensome. New technologies are needed to overcome these limitations. The current project aims to develop a new system for inducible control of gene expression using long-wavelength (700-750 nm) light. In addition to avoiding the side effects and costs associated with drug-based systems, light-inducible control offers the advantages of precise spatial and temporal targeting of individual tissues and cells. Light also avoids the uptake and transport requirements inherent in small molecule-based inducers. Our proposed strategy will exploit a photoreceptor class that is naturally responsive to long-wavelength light, and convert it
into a "molecular light switch" that controls transcription of target genes. The selected photoreceptor is also naturally photoreversible enabling the engineered transcriptional switch to exert an unprecedented level of transcriptional control. Successful development of this system has the potential not only to revolutionize inducible gene expression in mammalian cell culture, but is also likely to advance the study of transgenic expression in whole animals and the development of novel genetic therapies.
PUBLIC HEALTH RELEVANCE: Technologies enabling control of gene expression, whether in laboratory cultures or in whole organisms, play a critical role in public health. Controlled gene expression permits production of proteins for research and therapeutics, but it is also crucial to basic research on early cellular responses. This project aims to develop a new technology to exploit light, at the upper limit of the visible range, for the precise experimental control over gne expression, circumventing limitations of current systems that require the application of small-molecule drugs.